Dosing & Uses
Dosage Forms & Strengths
ertugliflozin/sitagliptin
tablet
- 5mg/100mg
- 15mg/100mg
Type 2 Diabetes Mellitus
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate
5 mg/100 mg PO qDay in morning initially; if additional glycemic control is needed and starting dose is tolerated, may increase to maximum dose of 15 mg/100 mg
Patients on ertugliflozin: Maintain ertugliflozin dose when switched to combination
Dosage Modifications
Concomitant use with insulin and insulin secretagogues may increase the risk of hypoglycemia; lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ertugliflozin
Renal impairment
- eGFR ≥60 mL/min/1.73 m²: No dosage adjustment necessary
- eGFR <30 mL/min/1.73 m²: Contraindicated
- End-stage renal disease or dialysis: Contraindicated
eGFR 30-60 mL/min/1.73 m²
- Initiation of ertugliflozin not recommended
- Continued use not recommended with persistent eGFR 30-60 mL/min/1.73 m²
Hepatic impairment
- Mild-to-moderate: No dosage adjustment necessary
- Severe: Not recommended
Dosing Considerations
In patients with volume depletion, correct this condition before initiating
Limitations of use
- Not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis
- Has not been studied in patients with a history of pancreatitis; unknown whether the drug increases risk for the development of pancreatitis
<18 years: Safety and efficacy not established
≥65 years: No dosage adjustment necessary
Patients aged ≥65 years had a higher incidence of adverse reactions related to volume depletion compared with younger patients
Elderly patients are more likely to have decreased renal function; because renal function abnormalities can occur after initiating ertugliflozin, and sitagliptin is known to be substantially excreted by the kidneys, renal function should be assessed more frequently
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10% (Ertugliflozin)
Female genital mycotic infections (9.1-12.2%)
1-10% (Ertugliflozin)
Volume depletion adverse effects (1.9-4.4%)
Male genital mycotic infections (3.7-4.2%)
Urinary tract infections (4-4.1%)
Headache (2.9-3.5%)
Vaginal pruritus (2.4-2.8%)
Increased urination (2.4-2.7%)
Nasopharyngitis (2-2.5%)
Back pain (1.7-2.5%)
Renal adverse effects (1.3-2.5%)
Weight decreased (1.2-2.4%)
Thirst (1.4-2.7%)
Frequency Not Defined (Sitagliptin)
Upper respiratory tract infection
Nasopharyngitis
Headache
Abdominal pain
Nausea
Diarrhea
Peripheral edema
Postmarketing Reports (Sitagliptin)
Hypersensitivity including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions
Hepatic enzyme elevations
Acute pancreatitis
Worsening renal function and acute renal failure
Bullous pemphigoid
Constipation
Vomiting
Headache
Myalgia
Pain in extremity
Back pain
Pruritus
Rhabdomyolysis
Warnings
Contraindications
Hypersensitivity
Severe renal impairment, end-stage renal disease, or dialysis
Cautions
Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin reported; promptly discontinue if pancreatitis suspected
Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary
Causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, with low systolic blood pressure, on diuretics, or who are elderly
Renal impairment may occur owing to intravascular volume contraction; before initiating, consider factors that may predispose patients to acute kidney injury, including hypovolemia, chronic renal insufficiency, CHF, and concomitant medications (eg, diuretics, ACE inhibitors, ARBs, NSAIDs); consider temporarily discontinuing ertugliflozin in any setting of reduced oral intake or fluid loss; monitor for signs and symptoms of acute kidney injury, and, if evident, discontinue drug promptly and institute treatment
Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization reported in patients receiving SGLT2 inhibitors
An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor; before initiating, consider factors that may predispose patient to increased risk of amputations (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)
Heart failure has been observed in cardiovascular outcomes trials for 2 other DPP-4 inhibitors; consider the risks and benefits prior to initiating treatment in patients at risk for heart failure (eg, those with a prior history of heart failure, a history of renal impairment), and observe these patients for signs and symptoms of heart failure during therapy
Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible
Serious hypersensitivity reported with sitagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome (see Contraindications)
Dose-related increases in LDL-C reported
Severe and disabling arthralgia reported in patients taking DDP-4 inhibitors; may occur at any time; symptoms relieved upon discontinuation
Bullous pemphigoid requiring hospitalization reported with DPP-4 inhibitors; patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor
No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent
Ketoacidosis
- Before initiating therapy, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse
- Consider temporarily discontinuing therapy for at least 4 days for patients who undergo scheduled surgery
- Consider monitoring for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery); ensure risk factors for ketoacidosis are resolved prior to restarting therapy
- Educate patients on signs and symptoms of ketoacidosis and instruct patients to discontinue therapy and seek medical attention immediately if signs and symptoms occur
Drug interaction overview
- Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or insulin secretagogue may be required
- Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
- Monitoring glycemic control with 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
- Coadministration with sitagliptin has shown a slight increase in digoxin AUC (11%) and mean peak drug concentration (18%); no dosage adjustment of digoxin require, but monitor appropriately
Pregnancy
Pregnancy
Ertugliflozin
- Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
- Data are limited in pregnant women and are not sufficient to determine a drug-associated risk of adverse developmental outcomes; there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
Animal data
- In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy; doses ~13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible
- There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin ~300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis
Sitagliptin
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sitagliptin during pregnancy
- Health care providers are encouraged to report any prenatal exposure by calling the Pregnancy Registry at 1-800-986-8999
Lactation
Not recommended while breastfeeding
Unknown if distributed in human breast milk
Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney
Because of the potential for serious adverse reactions in a breastfed infant, advise women that ertugliflozin/sitagliptin is not recommended while breastfeeding
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Ertugliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; lowers the renal glucose threshold (ie, the plasma glucose concentration which exceed the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion
Sitagliptin: Dipeptyl peptidase-IV (DPP-4) inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins increase insulin release and synthesis from pancreatic beta cells and reduce glucagon secretion from pancreatic alpha cells
Absorption
Ertugliflozin
- Peak plasma time: 1 hr (fasting); 2 hr (high-fat, high-caloric meal)
- Peak plasma concentration, steady-state: 81.3 ng/mL (5 mg qDay); 268 ng/mL (15 mg qDay)
- AUC, steady-state: 398 ng⋅hr/mL (5 mg qDay); 1,193 ng⋅hr/mL (15 mg qDay)
- Steady-state is reached after 4-6 days
- Bioavailability, 15 mg dose: ~100%
Sitagliptin
- Peak plasma time: 1 hr
- Bioavailability: 87%
Distribution
Ertugliflozin
- Vd, steady-state: 85.5 L
- Protein binding: 93.6%
- Blood-to-plasma concentration ratio of ertugliflozin: 0.66
Sitagliptin
- Vd: 198 L
- Protein binding: 38%
Metabolism
Ertugliflozin
- Major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to 2 glucuronides (pharmacologically inactive at clinically relevant concentrations)
- CYP-mediated (oxidative) metabolism of ertugliflozin is minimal (12%)
Sitagliptin
- Primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8
Ertugliflozin
- Half-life: 16.6 hr
- Clearance: 11.2 L/hr
- Excretion, oral [14C]-ertugliflozin solution: Feces (40.9%); urine (50.2%)
- Excretion, unchanged ertugliflozin: Feces (33.8%); urine (1.5%)
Sitagliptin
- Half-life: 12.4 hr
- Renal clearance: 350 mL/min
- Excretion: 87% urine; 13% feces
Administration
Oral administration
Take in the morning qDay, with or without food
Missed dose
- Take it as soon as you remember
- If it is almost time for scheduled next dose, skip missed dose and take the next regularly scheduled time
- Do not take 2 doses of ertugliflozin at the same time
Storage
Store at room temperature between 68-77°F (20-25°C)
Keep tablets dry
Store blister packs in the original package
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Patient Handout
Formulary
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